Red blood cell substitutes are drugs currently under development for use in oxygen transporting resuscitation fluids and thus decrease the ischemia which may be associated with massive surgery or trauma. This therapeutic approach, in addition to providing volume, crystalloid, colloid and oxygen, may reduce the frequency and severity of the shock syndrome associated with hypovolemic episodes by decreasing both the extent and duration of the ischemia. Used with blood and or packed red blood cells, modified hemoglobin solutions offer increased flexibility in the initial treatment of the hypovolemic episode and prevention of tissue ischemia.
Review of the clinical state intended for treatment with modified hemoglobin solutions includes a brief global view of hypovolemia. Increasing blood loss is initially compensated by increased heart rate and vasoconstriction mediated by the release of catecholamines. Tissue response to a minor reduction in the amount of blood received is to extract a greater portion of the oxygen carried.
As a greater volume of blood is lost, the capacity of the compensatory mechanisms is exceeded. When a critical volume loss is exceeded, the heart is unable to maintain output because of inadequate blood return. If at this point any fluid is given to expand the intravascular volume, the heart will continue to maintain sufficient cardiac output of blood to resume adequate oxygen delivery; however, the penalty is a decreased oxygen transporting ability because of dilution.
Finally with continued loss of blood, even with adequate volume expanders, the hemoglobin concentration falls to levels too low to transport adequate oxygen, and red blood cells or an oxygen-carrying surrogate must be transfused to maintain adequate tissue levels of oxygen.
The quantity of oxygen consumed is the minimum amount required for aerobic metabolism to meet the energy needs for the unit. When oxygen becomes limiting such that the energy requirements can no longer be met, the anerobic pathways are utilized to provide energy. These pathways are much less efficient, unable to meet the energy needs of the cell and produce a metabolic acidosis. The cell, deficient in energy, cannot maintain its membrane potential with the final result of fluid moving from the interstitial space into the intracellular space. The correlation of metabolic acidosis severity is positive with the amount of hypovolemia, its duration, and unsatisfactory resuscitation outcome.
The recommendation of the American College of Surgeons, Committee on Trauma includes the aggressive use of balanced salt solutions (crystalloid) and crossmatched red cells, or type-specific red cells, as clinically indicated during the initial assessment and resuscitation. Supplemental oxygen is encouraged to ensure arterial blood saturation. When appropriate the metabolic acidosis is treated to promote physiological function of hormonal and neural transmitters.
In summary, hypovolemia is an acute event, which soon causes the tissue to become ischemic. The degree, duration, and extent of the ischemia correlate positively with the progression to irreversible shock. Therapeutic intervention includes the correction of the cause for hypovolemia, and vigorous replacement of intravascular fluid similar to that which was lost.
Attempts to replace lost blood with donor blood and crystalloid solutions are standard clinical practice that have evolved during the last fifty years of medicine. Limitations of time, availability, age and viscosity with these solutions have prompted a recent search for still another oxygen carrying resuscitation fluid with the following physiological properties:
(1) Transports adequate amounts of oxygen to the tissue under ambient conditions. The victim inhales ambient air and does not become acidotic; venous oxygen tension stays above 40 mm of Hg.
(2) The solution should be oncotically active as whole blood with a pressure of 25-30 mm of Hg and osmotically active with a value of about 280-300 mOsm.
(3) The solution should have a viscosity equal to that of blood or less as measured in a physiological relevant system.
(4) The retention of the solution within the intravascular space should be a half-disappearance time of 12-48 hours. Most importantly, the mechanism of clearance should not cause an osmotic diuresis (renal) or reticuloendothelial dysfunction (hepatic).
(5) The solution should allow transfusion to all recipients without cross-matching or sensitivity testing.
(6) The solution should be free from disease agents such as bacteria and virus particles (hepatitis, AIDS and others).
(7) Storage properties of the solution or its active oxygen carrier should require minimum amounts of refrigeration and the useful life should be greater than one year.
Obviously the seven properties listed are based upon the desired properties of blood one wishes to keep and a few changes in the underdesired clinical complications encountered that prevent adequate therapy or satisfactory outcome.
An ideal blood substitute with oxygen transport capability must add substantial flexibility to the treatment of hypovolemia as experienced in trauma and massive surgery. First of all it must be immediately available for use in a variety of situations from battlefield to operating room and extracorporeal pump. The ideal product must have minimal acute side effects so that it may be used efficaciously by paramedics with confidence that the diagnostic picture for the subsequent treating physician is not further complicated. It must also be tolerated in large dosages so that adequate therapy does not cause organ system impairment of a delayed or chronic nature. Last but not least, it should not impair our ability to crossmatch blood products for subsequent use as available.